Solid polymeric microparticles enhance the delivery of siRNA to macrophages in vivo

Lee, Sungmun; Yang, Stephen C.; Kao, Chen‐Yu; Pierce, Robert H.; Murthy, Niren

doi:10.1093/nar/gkp758

Cited by 60 publications

(65 citation statements)

References 17 publications

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“…21 At specific time points, the microparticle suspensions were centrifuged at 10,000 rpm for 10 min and siRNA content in the supernatants for each time point was determined using RiboGreen assay.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic Aerosol Bioengineering of siRNA for the Treatment of Inflammatory Lung Disease by TNFα Gene Silencing in Macrophages

Kelly¹,

Yadav²,

Lawlor³

et al. 2014

Mol. Pharmaceutics

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The development of small interfering RNA (siRNA) to silence specific genes offers a new means of understanding and treating a range of respiratory diseases, including inflammatory lung disease. The alveolar macrophage (AM) is a key component of the inflammatory process in the lungs, associated with high levels of gene expression in inflammatory lung disease and therefore an attractive target for therapeutic siRNA. Delivery of siRNA to macrophages presents a significant delivery challenge, as fully differentiated alveolar macrophages are difficult to access and transfect. In this study we engineered particles suitable for inhalation that would efficiently transfect macrophages postinhalation. The process for encapsulation of siRNA in poly(lactic-co-glycolic acid) microparticles (MPs) was optimized using a double emulsion technique, and the resulting particles were characterized for size, shape, aerosol characteristics, encapsulation efficiency, and integrity of encapsulated siRNA. The cell uptake of the siRNA-loaded microparticles was determined by flow cytometry, confocal laser scanning microscopy (CLSM), and high-content analysis (HCA) with MPs capable of transfecting up to 55% of cells. Anti-TNFα siRNA-MPs were then prepared to study the functional activity of encapsulated siRNA in LPS-stimulated macrophages as a model of inflammation. The anti-TNFα siRNA-MPs were able to decrease TNFα expression by 45% over 48 h in the differentiated human monocytic cell line THP-1 compared to negligible knockdown using commercial transfection reagents and offered significant, sustained siRNA knockdown of TNFα in primary monocytes for up to 72 h.

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Section: Methodsmentioning

confidence: 99%

Therapeutic Aerosol Bioengineering of siRNA for the Treatment of Inflammatory Lung Disease by TNFα Gene Silencing in Macrophages

Kelly¹,

Yadav²,

Lawlor³

et al. 2014

Mol. Pharmaceutics

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“…29,30 Poly(cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK), a polyketal, is a promising material for constructing such drug carriers for inflammatory diseases and cancer, owing to its neutral degradation products and acid sensitivity. [31][32][33][34] Herein, we report the development of multifunctional FRβ-targeting pH-responsive nanocarriers loaded with Mtx (Scheme 1). The nanocarriers were composed of poly(lacticco-glycolic acid) (PLGA)-polyethylene glycol (PEG)-folic acid (FA), PCADK, and lipids (FA-PPLNPs).…”

Section: Introductionmentioning

confidence: 99%

Multifunctional folate receptor-targeting and pH-responsive nanocarriers loaded with methotrexate for treatment of rheumatoid arthritis

Zhao¹,

Zhao²,

Yu³

et al. 2017

IJN

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive cartilage and bone destruction. Activated macrophages that overexpress folic acid (FA) receptors play an important role in RA, due to their abundance in inflamed synovial membrane and joints. In an effort to deliver drugs to the inflamed tissues, multifunctional FA receptor-targeting and pH-responsive nanocarriers were developed. They were composed of lipids, polyethylene glycol (PEG)–poly(lactic- co -glycolic acid) (PLGA) forming a hydrophilic shell, FA around the hydrophilic shell as a targeting ligand, and poly(cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK) and PLGA as a hydrophobic core. PCADK also acts as a pH-responsive material. Methotrexate (Mtx) was encapsulated in the nanoparticles, which exhibited pH-responsive release in vitro. Cellular uptake and cytotoxicity experiments revealed that FA-PEG-PLGA/PCADK–lipid nanoparticles loaded with Mtx (FA-PPLNPs) exhibited superior cellular uptake and higher cytotoxicity to activated macrophages than PPLNPs/Mtx. The therapeutic effect of FA-PPLNPs/Mtx in RA was confirmed in an adjuvant-induced arthritis rat model. These results suggest that the multifunctional folate receptor-targeting and pH-responsive nanocarriers are promising for the treatment of RA.

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“…It is therefore highly desirable to design stimuli responsive drug carriers for controlled drug delivery, which can release drugs on arrival at the target site [27]. Several such drug delivery systems have been generated that are responsive to pH, temperature, magnetic field, and concentrations of electrolytes or glucose [26,28]. However, these stimuli-responsive systems tend to be more generalized and may not be specific to the affected area.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen peroxide-responsive copolyoxalate nanoparticles for detection and therapy of ischemia–reperfusion injury

Lee

Bae

et al. 2013

Journal of Controlled Release

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The main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury is the generation of high level of hydrogen peroxide (H2O2). In this study, we report a novel diagnostic and therapeutic strategy for I/R injury based on H2O2-activatable copolyoxalate nanoparticles using a murine model of hind limb I/R injury. The nanoparticles are composed of hydroxybenzyl alcohol (HBA)-incorporating copolyoxalate (HPOX) that, in the presence of H2O2, degrades completely into three known and safe compounds, cyclohexanedimethanol, HBA and CO2. HPOX effectively scavenges H2O2 in a dose-dependent manner and hydrolyzes to release HBA which exerts intrinsic antioxidant and anti-inflammatory activities both in vitro and in vivo models of hind limb I/R. HPOX nanoparticles loaded with fluorophore effectively and robustly image H2O2 generated in hind limb I/R injury, demonstrating their potential for bioimaging of H2O2-associated diseases. Furthermore, HPOX nanoparticles loaded with anti-apoptotic drug effectively release the drug payload after I/R injury, exhibiting their effectiveness for a targeted drug delivery system for I/R injury. We anticipate that multifunctional HPOX nanoparticles have great potential as H2O2 imaging agents, therapeutics and drug delivery systems for H2O2-associated diseases.

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Solid polymeric microparticles enhance the delivery of siRNA to macrophages in vivo

Cited by 60 publications

References 17 publications

Therapeutic Aerosol Bioengineering of siRNA for the Treatment of Inflammatory Lung Disease by TNFα Gene Silencing in Macrophages

Therapeutic Aerosol Bioengineering of siRNA for the Treatment of Inflammatory Lung Disease by TNFα Gene Silencing in Macrophages

Multifunctional folate receptor-targeting and pH-responsive nanocarriers loaded with methotrexate for treatment of rheumatoid arthritis

Hydrogen peroxide-responsive copolyoxalate nanoparticles for detection and therapy of ischemia–reperfusion injury

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